Nucleoside analogs in combination therapy of herpes simplex infections

ABSTRACT

A pharmaceutical product comprising a nucleoside analogue active against herpes simplex virus, such as acyclovir/valaciclovir or penciclovir/famciclovir, and an immunosuppressant, as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of herpes simplex virus infections.

[0001] This invention relates to the use of a nucleoside analogue activeagainst herpes simplex virus (HSV), in the treatment of herpes simplexvirus infections, and to pharmaceutical compositions containing the twocomponents.

[0002] The disease indication for herpes simplex subtype 1 (HSV-1) isherpes labialis (cold sores), and the disease indication for herpessimplex subtype 2 (HSV-2) is genital herpes.

[0003] Herpes Labialis is a common world-wide disease characterized byrepeated attacks of versicular eruptions most commonly recognised on thelips and perioral skin. Many patients report pain, swelling andsignificant cosmetic concerns associated with subsequent ulceration oflesions. Although generally a minor disease, in some patients theconsequences of frequent severe attacks can be debilitating. The diseaseis naturally self-limiting in immunecompetent individuals and recurrentepisodes last 7-10 days.

[0004] First infection with genital herpes may be severe (primary firstepisode) if the patient has no previous history of labial or genitalherpes infection, while a less severe disease occurs if any antibodyresponse is developed through previous exposure to HSV—non-primary firstepisode. The most common sequel to primary genital herpes infection isrecurrent disease. The attack rate varies greatly but is likely thatpatients will experience on average 4-5 episodes per year.Symptomatology in these episodes are characterised by painful lesionswhich progress from papules and vesicles through to ulcers and finallycrusts. Lesions may be accompanied by a range of symptoms includingpain, tenderness, itching and swelling of the affected area.

[0005] EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, thecompound of formula (A):

[0006] and salts, phosphate esters and acyl derivatives thereof, asantiviral agents. The sodium salt hydrate of penciclovir is disclosed inEP-A-216459 (Beecham Group p.l.c.). Penciclovir and its antiviralactivity is also disclosed in Abstract P.V11-5 p.193 of ‘Abstracts of14th Int. Congress of Microbiology’, Manchester, England 7-13 September1986 (Boyd et. al.).

[0007] Orally active bioprecursors of the compound of formula (A) are offormula (B):

[0008] (B)

[0009] and salts and derivatives thereof as defined under formula (A);wherein X is C₁₋₆ alkoxy, NH₂ or hydrogen. The compounds of formula (B)wherein X is C₁₋₆ alkoxy or NH₂ are disclosed in EP-A-141927 and thecompounds of formula (B) wherein X is hydrogen, disclosed in EP-A-182024(Beecham Group p.l.c.) are preferred prodrugs. A particularly preferredexample of a compound of formula (B) is that wherein X is hydrogen andwherein the two OH groups are in the form of the acetyl derivative,described in Example 2 of EP-A-182024, hereinafter referred to asfamciclovir.

[0010] The compounds of formulae (A) and (B) and salts and derivativesthereof have been described as useful in the treatment of infectionscaused by herpesviruses, such as herpes simplex type 1 and herpessimplex type 2. All references herein to penciclovir/famciclovir includepharmaceutically acceptable salts, such as the hydrochloride, andsolvates, such as hydrates.

[0011] When used herein the term ‘immunosuppressant’ includespharmaceutical agents such as cytotoxic agents such cyclophosphamide andcyclosporin A and corticosteroids such as hydrocortisone anddexamethasone and non steroidal anti-inflammatory agents.

[0012] In one preferred aspect, the immunosuppressant is cyclosporin A.

[0013] The anti-herpes simplex virus properties of nucleoside analoguessuch as penciclovir/famciclovir or ayclovir/valaciclovir are potentiallyenhanced by administering the compound in conjunction with animmunosuppressant. The rationale is that in mice infected with herpessimplex virus, treatment with an antiviral agent to achieve clearance ofthe virus is particularly effective when the mice are immunosuppressedwith cyclosporin A.

[0014] Accordingly, the present invention provides a pharmaceuticalproduct comprising a nucleoside analogue active against herpes simplexvirus, such as acyclovir/valaciclovir or penciclovir/famciclovir, and animmunosuppressant, as a combined preparation for simultaneous, separateor sequential use in the treatment and/or prevention of herpes simplexvirus infections.

[0015] The present invention also provides a method of treatment and/orprophylaxis of herpes simplex virus infections, which comprisesadministering to a human or animal subject, a nucleoside analogue activeagainst herpes simplex virus, such as acyclovir/valaciclovir orpenciclovir/famciclovir, and an immunosuppressant or a pharmaceuticallyacceptable salt or ester thereof.

[0016] The invention further provides the use of a nucleoside analogueantiviral active against herpes simplex virus, such asacyclovir/valaciclovir or penciclovir/famciclovir for the manufacture ofa medicament for administration in conjunction with an immunosuppressantor a pharmaceutically acceptable salt or ester thereof, for thetreatment and/or prevention of herpes simplex virus infections.

[0017] Co-administration of penciclovir/famciclovir with animmunosuppressant is particularly useful for the treatment of severeand/or prolonged herpes simplex virus infections.

[0018] The antiviral such as penciclovir/famciclovir and theimmunosuppressant or a pharmaceutically acceptable salt or esterthereof, may be administered as a single pharmaceutical compositioncomprising effective amounts of the two active ingredients.Alternatively the two active ingredients may be co-administered in theform of two separate pharmaceutical compositions for simultaneous orsequential use. Normally the active ingredients will be administeredseparately according to the normal dosage and administration regimen forthe ingredients given alone. Commencement of administration may beeither with the immunosuppressant or the antiviral.

[0019] The unit doses of the nucleside analogue may be administered, forexample, 1 to 4 times per day. The exact dose will depend on the routeof administration and the severity of the condition being treated, andit will be appreciated that it may be necessary to make routinevariations to the dosage depending on the age and weight of the patientand immunocompromised patients may require an increased dosage.

[0020] Immunosuppressants are administered according to the conventionalroute of administration for the immunosuppressant employed.

[0021] When the two active ingredients are administered as separatepreparations, they are preferably given enterally, such as orally orparenterally (e.g. intramuscularly or, more particularly,intravenously).

[0022] According to a further aspect the invention provides apharmaceutical composition, for use in human or veterinary medicine,comprising a nucleoside analogue active against herpes simplex virus,such as acyclovir/valaciclovir or penciclovir/famciclovir, and animmunosuppressant or a pharmaceutically acceptable salt or esterthereof.

[0023] Compositions according to the invention may be formulated inconventional manner using one or more physiologically acceptablecarriers or excipients. Thus the compositions may, for example, beformulated for oral, buccal, parenteral or rectal administration.Compositions for administration by the oral route, in the form of forexample tablets or capsules, are preferred.

[0024] Compositions for oral use such as tablets and capsules may beprepared by conventional means with pharmaceutically acceptableexcipients such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.lactose, micro-crystalline cellulose or calcium hydrogen phosphate);lubricant (e.g. magnesium stearate, talc or silica); disintegrants (e.g.potato starch or sodium starch glycollate); or wetting agent (e.g.sodium lauryl sulphate). Tablets may be coated by methods well known inthe art. Liquid preparations for oral administration may take the formof, for example, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g. sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia);non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol orfractionated vegetable oils); and preservatives (e.g. methyl orpropyl-p-hydroxybenzoates or sorbic acid). The preparations may alsocontain buffer salts, flavouring, colouring and sweetening agents asappropriate.

[0025] Preparations for oral administration may be suitably formulatedto give controlled release of one or both active ingredients.

[0026] For parenteral administration the compositions may be presentedin a form suitable for bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form e.g. insyringes, ampoules or in multi-dose containers, with an addedpreservative.

[0027] The compositions may take such forms as suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising and/or dispersing agents.Alternatively, the active ingredients may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

[0028] For rectal administration the compositions may be formulated assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0029] The topical route of administration is preferred for treatment ofherpes labialis and cream formulations are suitable, such as thatdescibed for penciclovir in WO 91/11187 (Beecham Group p.l.c.).

[0030] The pharmaceutical compositions of the invention may be preparedaccording to conventional techniques well known in the pharmaceuticalindustry. Thus, for example, the penciclovir/famciclovir and theimmunosuppressant may be admixed together, if desired, with suitableexcipients. Tablets may be prepared, for example, by direct compressionof such a mixture. Capsules may be prepared by filling the blend alongwith suitable excipients into gelatin capsules, using a suitable fillingmachine. Controlled release forms for oral or rectal administration maybe formulated in a conventional manner associated with controlledrelease forms. Creams and other formulations for topical administrationare formulated in conventional manner.

[0031] The compositions for use according to the invention may, ifdesired, be presented in a pack or dispenser device which may containone or more unit dosage forms containing the active ingredients. Thepack may for example comprise metal or plastic foil, such as a blisterpack. The pack or dispenser device may be accompanied by instructionsfor administration. Where the penciclovir/famciclovir and theimmunosuppressant are intended for administration as two separatecompositions these may be presented in the form of, for example, a twinpack.

[0032] It will be appreciated that an alternative anti-herpes simplexvirus nucleoside analogue such as ganciclovir, may be used in place ofacyclovir/valaciclovir or penciclovir/famciclovir in the presentinvention, at an appropriate dosage level according to its activity.

[0033] Information with respect to structure and activity of nucleosideanalogues hereinbefore may be obtained from well known pharmaceuticalindustry references, such as “Pharmaprojects”, PJB publications Limited,Richmond, Surrey, U.K. or from ‘R & D Focus’, isssued by IMS Worldpublications, 364 Euston Road, London NW1 3BL.

[0034] References to a anti-herpes simplex virus nucleoside analogue,including compounds described in the abovementioned patent referencesand the specific compounds mentioned hereinbefore and salts thereof,include solvates such as hydrates.

[0035] Examples of pharmaceutically acceptable salts are as described inthe aforementioned Patent references in the name of Beecham Group p.l.c.and references quoted therein, the subject matter of which areincorporated herein by reference.

[0036] Anti-herpes simplex virus nucleoside analogues may be identifiedby standard methods.

[0037] The following results from animal studies illustrate theinvention.

EXPERIMENTS IN MICE INFECTED WITH HSV-1 VIRUS

[0038] A cutaneous infection was established by inoculation of the earpinnae of mice with HSV-1 (SC16) and the effects of oral famciclovir andvalaciclovir on the latent virus infection was investigated.

[0039] BALB/c female mice (Bantin and Kingman, Kingston, Hull, UK) werepurchased at 3 to 4 weeks old and inoculated one week later. Virussuspension (10 ul) containing 5×10⁴ p.f.u. were inoculated into the skinof the left ear pinna. Skin thickness was measured daily in individualmice by means of an Engineers' micrometre screw gauge. (ref. Nash et al,1980, J. Gen. Virol. 48, 351-357). Mice were killed daily and tissuesremoved for virus assays. Other mice were 4 months and then killed. Thetrigeminal ganglia and cervical dorsal root ganglia were removed andco-cultivated. Those cultures showing virus replication were recorded aspositive.

[0040] In a first experiment, groups of immunocompetant mice wereuntreated (control), antiviral treatment was initiated on days 1, 2, 3,4 or 5 post-infection (p.i.) and and ceased on day 10 p.i. The compoundswere administered ad libitum in the drinking water, at 1 mg/ml(approximately 100 mg/kg/day).

[0041] In a second experiment, mice were immunosupressed withCyclosporin A (CyA) from day −2 to day =10 (day 0 being the day ofinfection). Groups of mice were untreated (control), or treated withfamciclovir orally at 50 mg/kg twice daily from 22 h after infection to5.5 or 10.5 days. The ganglia were examined for reactivation ofinfectious virus 1 or 4 months later.

[0042] The results show that in the second experiment, the effect oftreating with famciclovir or valaciclovir has a significantly greatereffect on virus replication and disease.

1. A pharmaceutical product comprising a nucleoside analogue activeagainst herpes simplex virus, and an immunosuppressant, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment and/or prevention of herpes simplex virus infections.
 2. Amethod of treatment and/or prophylaxis of herpes simplex virusinfections, which comprises administering to a human or animal subject,a nucleoside analogue active against herpes simplex virus, and animmunosuppressant or a pharmaceutically acceptable salt or esterthereof.
 3. The use of a nucleoside analogue antiviral active againstherpes simplex virus, for the manufacture of a medicament foradministration in conjunction with an immunosuppressant or apharmaceutically acceptable salt or ester thereof, for the treatmentand/or prevention of herpes simplex virus infections.
 4. A product,method, or use according to claim 1, 2 or 3, wherein the nucleosideanalogue is acyclovir/valaciclovir or penciclovir/famciclovir.
 5. Aproduct, method, or use according to claim 1, 2, 3, or 4, wherein theimmunosuppressant is a cytotoxic agents, a corticosteroid, or anon-steroidal anti-inflammatory agent.
 6. A product, method, or useaccording to claim 5 wherein the immunosuppressant is cyclophosphamide,cyclosporin A, hydrocortisone, or dexamethasone.